The etiology of inflammatory bowel disease is not well understood; however, there is evidence to support a genetic predisposition, a triggering antigen, and an abnormal immune response. NOD 2, a Crohn's disease susceptibility gene is the best studied genetic defect thus far. NOD 2 recognizes bacterial muramyl-dipeptide which leads to increased production of NFkB and other pro-inflammatory mediators. TLR4 is part of the innate immune system and seems to regulate the response towards enteric bacteria, specifically lipopolysaccharide (LPS), which is a component of gram negative bacterial cell walls (Gribar, S. C., et al. The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation. J. Leukoc Biol. 2008 March; 83(3):493-8). Enteric bacteria are thought to be the antigenic stimuli in inflammatory bowel disease (IBD). Specific genetic defects are likely responsible for the different phenotypic characteristics of IBD.
Lipopolysaccharide is a potent inducer of B cells, monocytes, and dendritic cells. Stimulation of these cells leads to the production of inflammatory cytokines so that the cells can participate in the immune response to bacterial pathogens (Wang, J. W., et al. Identification of a novel lipopolysaccharide-inducible gene with key features of both A kinase anchor proteins and chs1/beige proteins. J Immunol. 2001 Apr. 1; 166(7):4586; Kerr, W. G., et al. Transcriptionally defective retroviruses containing lacZ for the in situ detection of endogenous genes and developmentally regulated chromatin. Cold Spring Harbor Symposia on Quantitative Biology. 1989: 54, 767-776). In order to identify genes involved in the maturation of immune cells, a gene-trapping system using LPS as a stimulant of lymphocyte differentiation was developed. Several novel LPS responsive genes were successfully trapped from mammalian cells, including Lipopolysaccharide Responsive Beige-like Anchor (LRBA). (Kerr, W. G., et al. Analysis of lipopolysaccharide-response genes in B-lineage cells demonstrates that they can have differentiation stage-restricted expression and contain SH2 domains. Proc Natl Acad Sci. Vol 93 p. 3947-52; Kerr, W. G., et al. Cold Spring Harbor Symposia on Quantitative Biology. 1989: 54, 767-776). LRBA is involved in guiding intracellular vesicles to activated receptor complexes, facilitating polarized secretion and/or membrane deposition of immune effector molecules. The gene was then cloned and its promoter was studied; revealing binding sites for NFkB, p53 and E2F (Wang, J. W., et al. Deregulated expression of LRBA facilitates cancer cell growth. Oncogene. 2004 May 20; 23(23):4089-97).
The novel LPS-gene trapping system serves as an excellent tool to help identify genes that are involved in the immune regulation of bacteria (Kerr, W. G., et al. Proc Natl Acad Sci. Vol 93 p. 3947-52; Kerr, W. G., et al. Cold Spring Harbor Symposia on Quantitative Biology. 1989: 54, 767-776). Based on homology to the CHS1/BG gene and Protein Kinase A anchor proteins, LRBA and its paralogues (collectively referred to as the WBW gene family) are involved in directing trafficking of intracellular vesicles to activated receptor complexes and thus facilitating polarized secretion and/or membrane deposition of effector molecules in both the immune system and nervous system. There are at least three different isoforms of LRBA and the ratio of these isoforms varies dramatically in different tissues (Wang, J. W., et al. J Immunol. 2001 Apr. 1; 166(7):4586).